Scatter factor has previously been described as a cytokine which is secreted by fibroblasts (see Stoker et al., J. Cell Sci., Vol. 77, pp. 209-223 (1985) and Stoker et al., Nature (London), Vol. 327, pp. 238-242 (1987)) and by vascular smooth muscle cells (see Rosen et al., In Vitro Cell Dev. Biol., Vol. 25, pp. 163-173 (1989)). Scatter factor has been shown to disperse cohesive epithelial colonies and stimulate cell motility. In addition, scatter factor has been shown to be identical to hepatocyte growth factor (HGF) (see Weidner et al., Proc. Nat'l. Acad. Sci. USA, Vol. 88, pp. 7001-7005 (1991) and Bhargava et al., Cell Growth Differ., Vol. 3, pp. 11-20 (1992)), which is an independently characterized serum mitogen (see Miyazawa et al., Biochem. Biophys. Res. Commun., Vol. 169, pp. 967-973 (1989) and Nakamura et al., Nature (London), Vol. 342, pp. 440-443 (1989)). Scatter factor induces kidney epithelial cells in a collagen matrix to form branching networks of tubules, suggesting that it can also act as a morphogen (see Montesano et al., Cell, Vol. 67, pp. 901-908 (1991)).
Scatter factor (HGF) is a basic heparin-binding glycoprotein consisting of a heavy (58 kDa) and a light (31 kDa) subunit. It has 38% amino acid sequence identity with the proenzyme plasminogen (see Nakamura et al., Nature (London), Vol. 342, pp. 440-443 (1989)) and is thus related to the blood coagulation family of proteases. Its receptor in epithelium has been identified as the c-met protooncogene product, a transmembrane tyrosine kinase (see Bottaro et al., Science, Vol. 251, pp. 802-804 (1991) and Naldini et al., Oncogene, Vol. 6, pp. 501-504 (1991)).
Scatter factor has been found to stimulate endothelial chemotactic and random migration in Boyden chambers (see Rosen et al., Proc. Soc. Exp. Biol. Med., Vol. 195, pp. 34-43 (1990)); migration from carrier beads to flat surfaces (see Rosen et al., Proc. Soc. ExP. Biol. Med., Vol. 195, pp. 34-43 (1990)); formation of capillary-like tubes (see Rosen et al., Cell Motility Factors, (Birkhauser, Basel) pp. 76-88 (1991)) and DNA synthesis (see Rubin et al., Proc. Nat'l. Acad. Sci. USA, Vol. 88, pp. 415-419 (1991)). In addition, preliminary studies have suggested that scatter factor induces endothelial secretion of plasminogen activators (see Rosen et al., Cell Motility Factors, (Birkhauser, Basel) pp. 76-88 (1991)).
The term "angiogenesis", as used herein, refers to the formation of blood vessels. Specifically, angiogenesis is a multistep process in which endothelial cells focally degrade and invade through their own basement membrane, migrate through interstitial stroma toward an angiogenic stimulus, proliferate proximal to the migrating tip, organize into blood vessels, and reattach to newly synthesized basement membrane (see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)). These processes are controlled by soluble factors and by the extracellular matrix (see Ingber et al., Cell, Vol. 58, pp. 803-805 (1985)).
Because proteases, such as plasminogen activators (the endothelial secretion of which is induced by scatter factor) are required during the early stages of angiogenesis, and since endothelial cell migration, proliferation and capillary tube formation occur during angiogenesis, the inventors hypothesized that scatter factor might enhance angiogenic activity in vivo. In addition, it is desirable to enhance angiogenic activity so that wound healing and organ transplantation can be enhanced.
It is therefore an object of this invention to provide a method of enhancing angiogenic activity.
It is a further object of this invention to provide a method of enhancing wound healing.
It is a still further object of this invention to provide a method of enhancing organ transplantation.